Theoretical studies of the ATP hydrolysis mechanism of myosin

The ATP hydrolysis mechanism of myosin was studied using quantum chemical ( QM) and molecular dynamics calculations. The initial model compound for QM calculations was constructed on the basis of the energy-minimized structure of the myosin(S1dc)-ATP complex, which was determined by molecular mechani cs calculations. The result of QM calculations suggested that the ATP hydro lysis mechanism of myosin consists of a single elementary reaction in which a water molecule nucleophilically attacked gamma -phosphorus of ATP. In ad dition, we performed molecular dynamics simulations of the initial and fina l states of the ATP hydrolysis reaction, that is, the myosin-ATP and myosin -ADP(.)Pi complexes. These calculations revealed roles of several amino aci d residues (Lys185, Thr186, Ser237, Arg238, and Glu459) in the ATPase pocke t, Lys185 maintains the conformation of beta- and gamma -phosphate groups o f ATP by forming the hydrogen bonds. Thr186 and Ser237 are coordinated to a Mg2+ ion, which interacts with the phosphates of ATP and therefore contrib utes to the stabilization of the ATP structure. Arg238 and Glu459, which co nsisted of the gate of the ATPase pocket, retain the water molecule acting on the hydrolysis at the appropriate position for initiating the hydrolysis .